L2HGDH is a mitochondrial inner membrane enzyme that catalyzes the oxidation of L-2-hydroxyglutarate (L-2-HG) to α-ketoglutarate (αKG) 1. The enzyme contains FAD and NAD(P)-binding domains essential for its catalytic activity 2. L2HGDH deficiency causes L-2-hydroxyglutaric aciduria (L2HGA), a rare autosomal recessive neurometabolic disorder characterized by systemic L-2-HG accumulation 3. Affected individuals present with progressive neurological symptoms including psychomotor retardation, cerebellar ataxia, seizures, macrocephaly, and abnormal white matter changes on brain MRI 34. Mechanistically, L-2-HG accumulation impairs αKG-dependent histone and DNA demethylases (KDM5, TET enzymes), disrupting epigenetic regulation 5. This leads to excessive histone methylation, MYC oncogene activation, neural progenitor cell hyperproliferation, and defective neuronal differentiation 5. Mouse models demonstrate that L2HGDH loss causes leukoencephalopathy, neuroinflammation, and late-onset neurodegeneration 6. Clinically, diagnosis relies on elevated urinary/plasma L-2-HG levels, MRI findings, and L2HGDH mutational analysis 3. Over 70 pathogenic mutations have been identified, including frameshift and nonsense mutations causing protein truncation 74. L2HGA represents a metabolic disease where epigenetic dysregulation, rather than simple metabolite toxicity, drives neurological pathology.